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Molecular Pharmacology

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Research ArticleArticle

The Bioreduction of a Series of Benzoquinone Ansamycins by NAD(P)H:Quinone Oxidoreductase 1 to More Potent Heat Shock Protein 90 Inhibitors, the Hydroquinone Ansamycins

Wenchang Guo, Philip Reigan, David Siegel, Joseph Zirrolli, Daniel Gustafson and David Ross
Molecular Pharmacology October 2006, 70 (4) 1194-1203; DOI: https://doi.org/10.1124/mol.106.025643
Wenchang Guo
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Philip Reigan
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David Siegel
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Joseph Zirrolli
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Daniel Gustafson
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David Ross
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Abstract

We have previously evaluated the role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the bioreductive metabolism of 17-(allylamino)-demethoxygeldanamycin (17AAG) to the corresponding hydroquinone, a more potent 90-kDa heat shock protein (Hsp90) inhibitor. Here, we report an extensive study with a series of benzoquinone ansamycins, which includes gel-danamycin, 17-(amino)-17-demethoxygeldanamycin, and 17-demethoxy-17-[[2-(dimethylamino)ethyl]amino]-geldanamycin. The reduction of these benzoquinone ansamycins by recombinant human NQO1 to the corresponding hydroquinone ansamycins was monitored by high-performance liquid chromatography (HPLC) and confirmed by liquid chromatography/mass spectrometry. Inhibition of purified yeast Hsp90 ATPase activity was augmented in the presence of NQO1 and abrogated by 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl-]indole-4,7-dione (ES936), a mechanism-based inhibitor of NQO1, showing that the hydroquinone ansamycins were more potent Hsp90 inhibitors than their parent quinones. An isogenic pair of human breast cancer cell lines, MDA468 and MDA468/NQ16, differing in expression of NQO1, was used, and HPLC analysis showed that hydroquinone ansamycins were formed by the MDA468/NQ16 cells, which could be prevented by ES936 pretreatment. The MDA468/NQ16 cells were more sensitive to growth inhibition after treatment with the benzoquinone ansamycins compared with the MDA468 cells; this increased sensitivity could be reduced by ES936 pretreatment. The increased duration of benzoquinone ansamycin exposure showed increased potency and -fold inhibition in MDA468/NQ16 cells relative to the parental MDA468 cells. Computational-based molecular modeling studies displayed additional contacts between yeast Hsp90 and the hydroquinone ansamycins, which translated to greater interaction energies compared with the corresponding benzoquinone ansamycins. In conclusion, these studies show that the reduction of this series of benzoquinone ansamycins by NQO1 generates the corresponding hydroquinone ansamycins, which exhibit enhanced Hsp90 inhibition.

Footnotes

  • This work was supported by National Institutes of Health grant R01-CA51210.

  • W.G. and P.R. contributed equally to this work.

  • ABBREVIATIONS: Hsp90, heat shock protein 90; GM, geldanamycin; 17AAG, 17-(allylamino)-17-demethoxygeldanamycin; 17DMAG, 17-demthoxy-17-[[2-(dimethylamino)ethyl]amino]-geldanamycin; 17AG, 17-(amino)-17-demethoxygeldanamycin; NQO1, NAD(P)H:quinone oxidoreductase; 17AAGH2, 17-(allylamino)-17-demethoxygeldanamycin hydroquinone; ES936, 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl-]indole-4,7-dione; 17AEP-GA, 17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]-geldanamycin; DCPIP, 2,6-dichlorophenol-indophenol; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; BSA, bovine serum albumin; rhNQO1, recombinant human NQO1; HPLC, high-performance liquid chromatography; LC/MS, liquid chromatography/mass spectrometry; DMSO, dimethyl sulfoxide.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received April 12, 2006.
    • Accepted July 6, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (4)
Molecular Pharmacology
Vol. 70, Issue 4
1 Oct 2006
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Research ArticleArticle

The Bioreduction of a Series of Benzoquinone Ansamycins by NAD(P)H:Quinone Oxidoreductase 1 to More Potent Heat Shock Protein 90 Inhibitors, the Hydroquinone Ansamycins

Wenchang Guo, Philip Reigan, David Siegel, Joseph Zirrolli, Daniel Gustafson and David Ross
Molecular Pharmacology October 1, 2006, 70 (4) 1194-1203; DOI: https://doi.org/10.1124/mol.106.025643

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Research ArticleArticle

The Bioreduction of a Series of Benzoquinone Ansamycins by NAD(P)H:Quinone Oxidoreductase 1 to More Potent Heat Shock Protein 90 Inhibitors, the Hydroquinone Ansamycins

Wenchang Guo, Philip Reigan, David Siegel, Joseph Zirrolli, Daniel Gustafson and David Ross
Molecular Pharmacology October 1, 2006, 70 (4) 1194-1203; DOI: https://doi.org/10.1124/mol.106.025643
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